1. Field of the Invention
The present invention relates to phenoxypyridine derivative salts and crystals thereof that have inhibiting activity against hepatocyte growth factor receptor (hereinafter abbreviated as “HGFR”) and are useful as anti-tumor agents and inhibitors for cancer metastasis, and to processes for preparing the same.
More specifically, it relates to acid addition salts of N-(2-fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxyamide (formula (1) below, hereinafter referred to as “Compound 1”) or crystals thereof and to salts of N-{2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxyamide (formula (2) below, hereinafter referred to as “Compound 2”) or crystals thereof, and to processes for preparing them.

2. Related Background Art
Overexpression of HGFR is reported in various kinds of tumors such as a pancreatic cancer, a gastric cancer, a colorectal cancer, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a brain tumor, an ovarian cancer and an esophageal cancer (Non-patent documents 1 and 5). HGFR expressed in these cancer cells is considered to be involved in cancer malignancy (aberrant growth, invasion or enhanced metastasis), because HGFR causes autophosphorylation of intracellular tyrosine kinase constitutively or upon stimulation by hepatocyte growth factor (hereafter referred to as “HGF”).
It is also reported that HGFR is expressed in vascular endothelial cells and is involved in tumor angiogenesis since HGF stimulates HGFR to facilitate proliferation and migration of vascular endothelial cells (non-patent document 2).
Furthermore, NK4, an antagonistic peptide for HGF, is reported to block HGF-HGFR signal to inhibit invasion of cancer cells and tumor angiogenesis (non-patent documents 3 and 4).
Therefore, a compound having inhibitory activity against HGFR is expected to be useful as an anti-tumor agent, an angiogenesis inhibitor or an inhibitor for cancer metastasis.
Incidentally, Patent document 1 discloses phenoxypyridine derivatives having inhibitory activity against HGFR and processed for preparing the same, but neither discloses nor suggests Compound 1 and Compound 2, nor salts of Compound 1 and Compound 2 or crystals thereof, nor processes for preparing the same.    [Patent document 1] WO 2005/082855    [Non-patent document 1] Oncology Reports, 5, 1013-1024 (1998)    [Non-patent document 2] Advances in Cancer Research, 67, 257-279 (1995)    [Non-patent document 3] British Journal of Cancer, 8, 864-873 (2001)    [Non-patent document 4] Cancer Sci., 94, 321-327 (2003)    [Non-patent document 5] Oncogene, 25(3), 409-418 (2006)